1. Field of the Invention
The present invention relates to a process for producing decahydro(4aS, 8aS)isoquinoline-3(S)-carboxamides of formula (4) that are useful as an intermediate of Saquinavir (U.S. Pat. No. 5,451,678, also E.P. 432694) which is an anti-AIDS agent owing to the excellent HIV protease inhibition activity.
2. Description of the Background
U.S. Pat. No. 5,256,783 describes a method of producing decahydro(4aS, 8aS) isoquinoline-3(S)-carboxamides, by producing N-tertbutyldecahydro(4aS, 8as)isoquinoline-3(S)-carboxamide in which an amide is introduced into tertbutylamide. The method described in this patent comprises five steps (1) N-protecting L-phenylalanine with benzyl chloroformate, (2) forming a mixed acid anhydride into N-tertbutylamide (84.3%), (3) reacting the resulting amide with formaldehyde in the presence of an acid catalyst to form a tetrahydroisoquinoline compound (66%), (4) N-deprotecting this compound by catalytic reduction using Pd (79%), and (5) obtaining a decahydroisoquinoline compound using an Rh catalyst (59%). However, this method is problematic in that it requires many steps, it has a step with a low yield, Rh is expensive and the reaction has to be strictly controlled to maintain optical purity. Accordingly, the development of a simpler method is desirable.
Further, non-uniform metal catalysts such as Rh, Pt or the like are expensive and are used in nuclear reduction of aromatic rings having functional groups. In contrast, Ru is inexpensive and also causes nuclear reduction of an aromatic ring. However, Ru can only be used in a nuclear reduction of an aromatic ring of a compound free of functional groups, such as toluene or the like. In addition, the influence on the optical activity or the sterically selective reduction is not known.
On the other hand, Chimika Chronika, New Series, 18, 3, 1989 teaches a method of producing tetrahydroisoguinoline-3-carboxamide (the above-mentioned intermediate), wherein tetrahydroisoquinoline-3-carboxylic acid is protected with a benzyloxycarbonyl group (66.5%), the resulting compound is converted into NCA with phosphorus pentachloride (69%), and NCA is reacted with an amine to form an amide (57%). However, since this method is conducted using a racemic compound, it is unclear whether or not optical activity is maintained, the yield in each step is low, and undesirable by-products and industrial waste are formed in large amounts. Accordingly, this method is not industrially useful.